The bisphosphonates are a new class of drags which have been developed during the past two decades for diagnostic and therapeutic use in various diseases of bone and calcium metabolism. Papapoulos describes therapeutic bisphosphonates as falling into three categories: first generation drugs typified by etidronate, which have significant activity but do not predictably suppress bone resorption; second generation agents such as pamidronate which cause predictable resorption suppression when given parenterally, but are hampered in oral formulations by low absorption and GI toxicity, and a third generation with both oral and parenteral efficacy. Fleisch indicates that bisphosphonate compounds are the drugs of choice in tumor induced bone disease and that the relatively few adverse events that have been associated with their use are specific for each compound.
The three compounds commercially available for use in tumor induced bone disease are in order of increasing potency, 1-Hydroxyethylidene-bisphosphonic acid (etidronate), Dichloromethylene-bisphosphonic acid (clodronate), and 3-Amino-1-hydroxypropylidene-bisphosphonic acid (pamidronate). Other bisphosphonate compounds known in literature to have been administered to humans include 4-Amino-1-hydroxybutylidene-bisphosphonic acid (alendronate), 6-Amino-1-hydroxyhexylidene-bisphosphonic acid, (4-Chlorophenyl)thio-methylidene-bisphosphonic acid (tiludronate), 2-(3-pyridinyl)-1-hydroxyethylidene-bisphosphonic acid (risedronate), and 1-Hydroxy-3-(methylpentylamino)-propylidene-bisphosphonic acid (BM 21.0955).
The individual bisphosphonates exhibit varying degrees of gastrointestinal toxicity. The pronounced GI toxicity of pamidronate is well documented and use of enteric coated tablets of pamidronate in clinical studies was disclosed by Reid et al. PCT Publication No. WO 93/09785 discloses enterically-coated dosage forms of the drug risedronate, one embodiment of which is a compressed tablet of active ingredient directly coated with a single layer of enteric polymer. The absence of prior art suggesting enteric coated dosage forms for bisphosphonates other than pamidronate and risedronate may reflect lower degrees of G.I. toxicity exhibited by some of these compounds or the fact that the low absorption of some of these compounds through the gastrointestinal tract has made IV infusion the favored mode of administration. The greater antihypercalcemic activity and GI absorption of newer compounds makes oral administration increasingly attractive. Although these other bisphosphonates may not exhibit the same degree of GI toxicity as pamidronate, they nonetheless may produce gastric irritation in particularly sensitive individuals. Enteric-coated dosage forms for these other bisphosphonate compounds may provide a solution to this problem. In order to maximize absorption of active, it is desirable that such a dosage form release the active in the proximal portion of the lower G.I. tract, preferably in the small intestine. This requires that the enteric film be soluble at pH 5.5 or greater as typically present in the small and large intestines. Enteric coated dosage forms can suffer from stability problems as a result of interactions between the active drug and the acidic enteric coating. In particular, bisphosphonate compounds which have a basic nitrogen containing moiety are susceptible to interaction with acidic carboxyl groups present in the enteric coating polymer. The present invention solves the above problems by providing a novel enteric-coated dosage form comprising a core tablet containing a therapeutically effective amount of bisphosphonate, a stability enhancing subcoat which minimizes migration of active from core tablet to the surface of the enteric coating, and an enteric film specifically formulated to rapidly and completely dissolve once the dosage form enters the proximal portion of the lower gastrointestinal tract.